Sequences of 234 complete genomes and 631 hepatitis B surface antigen genes were used to assess the worldwide diversity of hepatitis B virus (HBV). Apart from the described two subgenotypes each for A and F, also B, C, and D divided into four subgenotypes each in the analysis of complete genomes supported by significant bootstrap values. The subgenotypes of B and C differed in their geographical distribution, with B1 dominating in Japan, B2 in China and Vietnam, B3 confined to Indonesia, and B4 confined to Vietnam, all strains specifying subtype ayw1. Subgenotype C1 was common in Japan, Korea, and China; C2 in China, South-East Asia, and Bangladesh, and C3 in the Oceania comprising strains specifying adrq–, and C4 specifying ayw3 is encountered in Aborigines from Australia. This pattern of defined geographical distribution was less evident for D1–D4, where the subgenotypes were widely spread in Europe, Africa, and Asia, possibly due to their divergence having occurred a longer time ago than for genotypes B and C, with D4 being the first split and still the dominating subgenotype of D in the Oceania. The genetic diversity of HBV and the geographical distribution of its subgenotypes provide a tool to reconstruct the evolutionary history of HBV and may help to complement genetic data in the understanding of the evolution and past migrations of man.

The prevalence in the population of hepatitis B virus (HBV) surface antigen (HBsAg) variants that may impair diagnosis, or allow the virus to escape vaccine‐induced immunity or passive immunoglobulin therapy is unknown. A genome fragment encoding HBsAg amino acids 112–212 was amplified and sequenced from the sera of 272 unselected DNA‐positive, HBV‐chronic carriers from Spain. The genotype and the HBsAg subtype were predicted from the sequences. Analysis of amino‐acid positions 112–157 revealed single or multiple substitutions in 39% of the carriers studied. Mutations were not detected for residues 121, 135, 137, 139, 140, 141, 142, 146, 147, 148, 149, 151, 152, 153, 155, 156, and 157. Substitutions reported previously to be in association with failures of diagnostic tests or with vaccine or immunoglobulin therapy escape were found in 12.5%, 6.6%, and 9.2% of carriers, respectively. Met133Thr (2.2%); Gln129His, Met133Ile, Phe/Tyr134Asn (1.8%); Phe/Tyr134Leu, Gly145Ala (1.5%), and Pro120Thr (1.1%) were the most frequent. Other substitutions, including Gly145Arg (0.4%), were found at a frequency of less than 1%. Samples containing HBV mutants were tested with three commercial assays for HBsAg screening. Almost all the mutants reacted to the upper cut‐off values of the assays, but six samples with weak reactivity with one or more of the methods were also found. Thus, HBV mutants with a potential impact on clinical and public health issues are moderately frequent among chronic carriers from Spain, although their influence on the performance of diagnostic tests seems to be slight. J. Med. Virol. 78:24–36, 2006. © 2005 Wiley‐Liss, inc.

Hepatitis B virus (HBV) is a human DNA virus, which replicates through an RNA intermediate because of the reverse-transcriptase (RT) activity of its DNA polymerase. As a result, the mutation rate for HBV is higher than the rate observed for most DNA viruses. HBVs are classified into genotypes based on genomic sequencing, and antigenic subtypes based on the antigenic properties of its major surface glycoprotein, the HBV surface antigen (HBsAg). Subgenotypes have been identified within most of the HBV genotypes. The HBV groups defined by the different genotype-HBsAg subtype associations found over the world display characteristic geographical distributions, reflecting the movements of human populations and other epidemiologically significant events. Such HBV groups constitute genetically stable viral populations sharing a common evolutionary history, but additional stable changes, originating from mutation and mutant selection, are observed within all of them. These viral sub-populations are known as the HBV variants, and some of which have medical and public health relevance. Pre-core (pre-C) defective variants have been shown to make HBV infection much less susceptible to interferon treatment, and treatment failures with other antiviral drugs have been associated with selection of resistant variants that display specific mutations in the genome region encoding the viral RT activity. Since the RT region of the genome overlaps the sequence encoding the HBsAg molecule, selection of drug resistant variants involves, in some cases, the indirect selection of HBsAg variants. Viral variants displaying changes in HBsAg seem to be very common among chronic HBV carriers; and some of these variants may emerge under the pressure of the neutralizing antibody response, leading to vaccine resistance and resistance to immunotherapy. Mutations conferring resistance to immunotherapy are noted often among liver transplant recipients and among babies born to HBV-carrier mothers. In addition, some of these HBsAg variants have been associated with lack of detection by HBsAg tests used for the diagnosis of HBV infection, for the identification of chronic carriers, for screening of blood donations for transfusion, and in the manufacture of therapeutic blood products.

Data reported during recent years reveal the complex picture of the epidemiology of hepatitis E virus (HEV) infection in Latin America. Whereas in countries like Argentina and Brazil is almost identical to the characteristic of most countries from North America and Europe, HEV in the Caribbean and Mexico involves the water-borne, non-zoonotic viral genotypes responsible for epidemics in Asia and Africa. Nevertheless, Latin America has been considered a highly endemic region for hepatitis E in the scientific literature, a generalization that ignores the above complexity. In addition, reports from isolated Amerindian communities, which display well known, important and very specific epidemiological features for hepatitis B and D virus infections are neither taken into account when considering the epidemiology of hepatitis E in the region. This review updates compilation of the available information for the HEV infection, both among humans and other mammals, in Latin America, discusses the strengths and the weaknesses of our current knowledge, and identifies future areas of research.

Chronic hepatitis E virus infection with rapid progression to cirrhosis is reported in 2 human immunodeficiency virus (HIV)-infected patients with severe immunosuppression. Monotherapy with ribavirin led to temporary viral response and marked improvement of liver damage. Chronic hepatitis E should be regarded as another opportunistic event within HIV infection.

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Hepatitis E virus (HEV) causes hepatitis E, an acute liver disease displaying diverse epidemiological patterns that correlate with the genetic diversity of the virus. Only a few strains have been characterized to date from cases of hepatitis E in Spain. Using three sets of new, HEV-specific primers, viral genome fragments were amplified from serum samples from 13 patients with acute hepatitis in different regions of Spain. Direct sequencing of these fragments and analysis of sequences lead to identify six genotype 1, six genotype 3, and one genotype 4 viral strains. Genotype 1 sequences were found in the clade with subtype 1a strains, and were amplified from travelers from India and Bangladesh, and from an African immigrant. Genotype 3 sequences were found in the clade with subtype 3f strains, were always amplified from patients who did not travel abroad recently, and were closely related to sequences from swine strains isolated in Spain. Patients infected by these strains lived in different regions and were mainly men aged above 50 years. The single genotype 4 sequence detected was amplified from a traveler returning from Vietnam. Hepatitis E is both an imported and an autochthonous disease in Spain, and closely related HEV genotype 3f strains are responsible for infections acquired locally in different regions of the country within a given time. Studies involving a significant number of human, swine, and environmental viral strains collected prospectively are, however, required in order to confirm a swine origin for autochthonous HEV genotype 3 human infections.

In a survey of hepatitis B virus (HBV) subtypes using one set of monoclonal typing antibodies, 96.6% of the samples were ad or ay and 3.3% (31) were untypeable. Using two additional antibody panels, 23 samples were ay and ad. Six samples required a third panel to be typed as ay. One sample was not typeable. These last 7 samples were nonreactive or had low reactivity with some antibodies to the common a determinant. Sequencing the HBsAg gene of these 7 samples revealed that amino acid (aa) 122 was arginine, as expected for the y determinant. However, mutations giving rise to serine at aa 120, leucine at aa 143, and glutamic acid at aa 144 were found singly or in combination and correlated with the monoclonal antibody binding patterns. These results have implications for further subtyping surveys, vaccines, immunotherapy, and the design of diagnostic assays, and they give clues to the structure of the major neutralizing epitope of HBV.